ADONIS 081593199100042V
Journal of Castromterology and Hepatology (1991) 6, 244-251
The Sydney System: Epidemiology and natural history of chronic gastritis P E N T T I SIPPONEN, M A T T 1 KEKKI A N D MAX SIURALA Department of Pathology, Jorvi Hospital, Espoo, Finland
INTRODUCTION Chronic gastritis (CG) has been a target of research for more than 100 years. Until now, its nature and relationship with gastric diseases have remained mysterious. The significance of C G has been re-emphasized, however, in recent years, because it has become apparent that C G is commonly associated with important gastric diseases such as gastric carcinoma or peptic ulcer diseases.’-’ In addition, most recent studies suggest that in most patients C G is a bacterial (microbial) disease, and that a successful treatment of the infection results in improvement of gastritis.6-10This has important therapeutic implications, particularly with respect to peptic ulcer disease.
NATURAL C O U R S E Chronic gastritis starts as an accumulation of inflammatory round cells in lamina propria of the gastric mucosa. These round cells are immunocompetent cells, mainly lymphocytes and IgA, IgG and IgM secreting plasma cells. Granulocytes often accompany CG and invade the lamina propria and the surface epithelium focally or diffusely (“active chronic gastritis”).ll This inflammatory stage of CG is commonly termed and referred to as “superficial gastritis” in the former literature. I n a number of subjects, gastritis may further progress to atrophy, “atrophic gastritis”, this stage of the process being characterized by an increasing loss of normal glands and by a growth of new metaplastic glands (intestinal, pseudopyloric metaplasias) in the underlying affected mucosa.” The C G is a peculiarly stable, persistent inflammatory response. Recent evidence suggests that this response is directed against specific bacterial organisms, Helicobacter pylori (HP), or, more rarely, against some other spiral organisms which colonise the surface of the gastric mucosa. 6*12 Without specific treatment CG is a life-long disease.13 However, in some rare patients C G may slow down and even heal, particularly in the antral mucosa. More often, C G remains stable, or progresses to gastritis with atrophy. l3 The long-term biopsy follow-up of Finnish and Estonian outpatient and population samples provide rough estimates of the natural course of C G (Table l).14-17 In some instances, C G appears in childhood, but is of slight degree and may heal spontaneously.” The next event is the appearance of CG in 15-30 year age group. In this phase,
C G affects both antrum and corpus, but usually affects the antrum more severely. Typically, at this age range, gastritis is a simple chronic inflammation and is accompanied by the presence of H P and serological antibody response against this bacterium in most cases.18 T h e diffuse HP-related chronic “pangastritis” (chronic gastritis in antrum and body) continues with increasing severity in middle age range ( 3 0 4 0 years) and is still present in the old age range (>61 years). In the development of atrophy there appears a dispersion of the process to three dissimilar topographic phenot y p e ~ in : ~ some ~ cases the distinct atrophic changes are limited to the antrum (antral gastritis with atrophy; former “B gastritis”), corpus (corpus gastritis with atrophy; former “A gastritis”), or they may affect antrum and corpus simultaneously (pangastritis with antral and corpus atrophy; former “AB gastritis”). The mean prevalence of the different phenotypes in the expression of C G in a Finnish adult population sample (mean age 46 years) is presented in Fig. 1. The final stage in the development of atrophy is total gastric atrophy. Although the speed of progression of Table 1 Summary of characteristics of chronic gastritis in different age groups of the general population Age group
Features of gastritis
Childhood ( < 15 years)
HP-associated antral gastritis. Gastritis is rare and mild. Tendency to heal.
Young age (15-30 years)
HP-associated antral gastritis or pangastritis are rather common. Atrophy is rare.
Middle age (30-60years)
HP-associated antral gastritis or pangastritis are common. Appearance of topographically different types of chronic gastritis with atrophy, that is, antral, corpus or pangastritis with coexistent atrophic changes in the underlying mucosa
Old age (61 +years)
All types of gastritis with atrophy are common. Autoimmune-type corpus gastritis with severe atrophy is not infrequent.
Correspondence: Dr P. Sipponen, Department of Pathology, Jorvi Hospital, 02740 Espoo, Finland. Accepted for publication 14 December 1990.
The Sydney System: Epidemiology of chronic gastritis
245
gastritis varies between individuals, in general, the process is very slow, and the time needed for the development of total gastric atrophy may be several decades. Studies in Finland suggest that the mean annual transition risk (per cent/year)of a subject to get antral or corpus gastritis is about 3 per 100, and is approximately of the same magnitude in the further progression of gastritis from simple chronic gastritis without atrophy to that one which accompanies atrophic changes (chronic gastritis with atrophy) (Fig. 2). In the further progression of gastritis to even more atrophic stages, it may be that the speed increases along with the increase in extent of the p r o c e ~ s . ~ ~ ' ~ ~
Chronic antral gastritis with or without accompanying atrophy is clearly HP-related. The bacteria are, however, usually absent in chronic corpus gastritis (corpus gastritis with severe corpus atrophy in particular)?l On the other hand, serum antibodies for HI? may occur also in this typeZZ but are seldom present, indicating that the p u r e corpus gastritis is unlikely to be HP-dependent in origin. On the whole, chronic corpus gastritis with moderate or severe atrophy (former "A gastritis") represents only a minor proportion (1-2*,) of subjects in the entire pool of CG patients, suggesting that most CG cases are linked with the acquisition of an HP infection (Table 1, Fig. 1).
GASTR IT I S WITHOUT ATROPHY
WITH ANTRAL ATROPHY 6%
I
56%
WITH CORPUS ATROPHY 2%
\
WITH ANTRAL AND CORPUS 4% ATROPHY
Figure 1 Prevalenceof different types of chronic gastritis in a Finnish population sample (males and females together; mean age 46 years; data collected in 1975-77). Data from Kekki et ~ 1 . ' ~
ANTRAL MUCOSA
3.5 OO/
CORPUS MUCOSA
3.3Q/'
3.3 %
Figure 2 Scheme presenting the mean annual risk to a subject of contracting chronic gastritis and, further, of contracting chronic gastritis with coexistent atrophy in the general population. Data from studies on gastritis in the general asymptomatic Finnish population.20
P. Sipponen et al.
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Although CG is virtually always related to HP at the start of the process, the further progression of CG from ga.;tritis without atrophy t o that one which accompanies atrophy seems to be less HP-dependent.z1.23The prevalence and grade of HP colonization steadily decrease parallel with the progression of atrophy. This indicates that factors other than bacteria may also influence the course of CC ; . 2 J Such Iic.tors can be genetic, macro-environmental (cg., nitrogen containing compounds, dietary factors, drugs) or micro-environmental (e.g., duodenogastric reflux, intragastric formation of nitrosocompounds) although the evidence from such processes is still far from convincing. Genetic factors certainly affect the course of CG, although the role of these factors, may vary in different topographical types of g a ~ t r i t i s . ~In~ the . ~ ~pathogenesis -~~ of corpus gastritis with atrophy (“A gastritis”), there is a dominantly inherited major factor which determines the ~ development of atrophy of the corpus m u c o ~ a . ’This factor seems to operate alone or in association with other closely related factors (genes).15 There also is some evidence that a recessively inherited parameter exists in the pathogenesis of chronic antral gastritis with atrophy (“B g a s t r i t i ~ ” ) .Genetic ~ ~ . ~ ~ factors may also occur in the genesis of pangastritis (“AB gastritis”) but these factors are even less well known.” ‘Thepresence of specific mechanisms in the pathogenesis of the three topographic phenotypes of chronic gastritis with atrophy have been demonstrated by the family behaviour of gastritis (15, 25). When a phenotype of chronic gastritis with accompanying atrophic alterations is chosen as an index, it appears that the same phenotype tends to occur more often than expected in the first degree relatives of the index subject, and the other phenotypes are less common than expected.1s In addition to the three topographic types in the expression and progression of gastritis, C G may also show heterogeneity in other respects. Gastritis, particularly gastritis with atrophy of mild degree, may be markedly patchy in antrum and corpus. Some areas of the stomach, like the angulus and the lesser curve, seem to be more liable to atrophy than the other In addition, the progression of gastritis in the antrum and corpus may occur in particular directions; as pyloro-cardiac or cardio-pyloric extensions of the original lesion.2s With regard to gender, there are no distinct differences in the natural course of C G between males and fern ale^.'^*^^ However, some studies tentatively suggest that the male gender shows a slightly higher liability toward gastritis than the female gender, but only at very early stages of the process.15
PREVALENCE The prevalence of CG in the population is strongly dependent on age. This total prevalence of C G and the prevalence of CG accompanied b y atrophic stages in antrum and corpus increase with age (Fig. 3). C G is rare in children in Western countries, but its frequency rises later rather linearly by age. On average, over one half of the population, even in industrialised Western countries, has C G of some degree in age groups above 50-60 years. Population-based reliable endoscopical and histological studies on gastritis are few in number. A group of studies,
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Figure 3 Age-specific prevalence of chronic gastritis (M) with and ( E l ) without atrophy in antral (upper picture) and corpus (lower picture) mucosa. From a sample representing the general Finnish population.I9
presenting the age-specific prevalence of C G in five These data European countries is shown in Fig. 4.19r29-31 demonstrate that CG is, indeed, very common in all populations in general, and that the greatest differences in prevalence of C G seem to occur in young and middle age. Extrapolation of the data in Fig. 4 would suggest that nearly the whole population in all five countries may have C G in age groups of 80 years or above. The detection of serum HP-antibodies has provided new possibilities for comprehensive epidemiological studies on HP-related gastritis. These studies have shown good concordance between endoscopically and serologically determined gastritis, and have confirmed that the frequencies of HP infection and of subsequent gastritis are usually very high, but that the rates of HP infection and gastritis also vary enormously in different parts of the world (Fig. 4).32-36 Based on these epidemiological data, it is likely that the prevalence of HP-related gastritis is dependent on the socioeconomic status of the pop~lation,~’ suggesting that an acquisition of the infection seems to be frequent in populations, or in countries, with a low standard of environmental hygiene, compared with those with high standards of living. It has become apparent, further, that in addition to the total C G prevalence, the mean age of onset of the HP infection may also be an important epidemiological variable.33p37Populations with high CG prevalence usually show an early onset of the infection, and vice versa (Fig. 4). It is tempting to speculate that chronic gastritis with
The Sydney System: Epidemiology of chronic gastritis
247
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Figure 4 Age-specific prevalence of (a) endoscopically and histologically determined gastritis and (b) age-specific prevalence of HP antibodies in different populations and c o u n t r i e ~ . ’ ~ ~ ~ ~ - ~ ~
marked atrophic changes is common in such populations in which a great proportion of subjects are infected at an early age, and in which time is, therefore, long enough for the development of atrophy in a significant proportion of the population. Correspondingly, it may be anticipated that the rate of the gastritis-related diseases is also high in such populations. This seems, indeed, to be the case. In a study in different provinces of China it has been shown recently that a high prevalence and an early onset of HP infection correlates with high incidence of gastric cancer.38 These observations are in good agreement with the earlier endoscopical and histological findings that a positive relationship exists between incidence of gastric cancer and degree and prevalence of chronic gastritis and atrophy (and intestinal metapla~ia).”*~~
RELATION OF FUNCTION OF GASTRIC MUCOSA Chronic gastritis, particularly chronic gastritis which accompanies atrophic changes in the underlying mucosa, profoundly affects the function of the stomach. Pentagastrin stimulated acid output is decreased already in mild corpus atrophy, and it decreases linearly with further loss of normal oxyntic glands, i.e., with progression of atrophy similar decrease is also evident in in the corpus m ~ c o s aA. ~ ~ fasting levels of serum pepsinogen I and in the output of intrinsic factor, suggesting that the atrophy leads to a general impairment in physiological functions of the gastric m ~ c o s a . ~ ~ The relationship between histology and function is not limited to the corpus mucosa only. A corresponding rela-
tionship exists also between antral gastritis and function of of atrophy in antral the antral m u c o ~ a ; development ~~*~~ mucosa results in decreased fasting and stimulated outputs of gastrin from antral G cells. Recent observations suggest that the H P itself may also have gastritis-independent actions on gastric functions.44 The HP is a urease-rich bacterium and produces ammonia from endogenous urea: a consequence may be that a HPdependent production of base in the stomach is high enough to neutralize acid produced in fasting conditions, thus resulting further in a release of gastrin from the antral G cells. Gastritis and H P colonization may impair mucosal resistance, although our knowledge in this respect is scanty.6 An acute erosive inflammation in HP-related gastritis may lower the epithelial integrity. The bacterium itself may also have noxious effects on the mucous layer and on the surface epithelial cells: the H P may secrete cytotoxic substances and enzymes with proteolytic and lipolytic proper tie^.^^
RELATIONSHIP TO GASTRIC DISEASES CG is asymptomatic in general but may be associated with several symptomatic gastric diseases.*946 The biological and clinical importance of chronic gastritis lies in that gastritis seems to be strongly associated with some important gastric diseases, such as gastric cancer or peptic ulcer disease, or, at least, is linked with an increased risk of these disorders. Estimations of the risk of peptic ulcer and gastric cancer in chronic gastritis are presented in Tables 2 and 3.
P . Sipponen et al.
248
Table 2 Estimation of age-adjusted relative risk of gastric cancer. Data from S a r o ~ i e k ~ ~ Type of chronic gastritis
Risk of gastric cancer (RR)*
Normal antral and corpus mu-
1"
cosa, or chronic pangastritis inrthout cncYi\Icrit
atrophy)
Chronic corpus gastritis with severe atrophy in the corpus
4.6 (l.slO.9)
muc05a
Chronic antral gastritis with severe atrophy in the antral mucosa
18.1(4.1-80.1)
Chronic pangastritis, with severe atrophy in both antral and corpus mucosa
approx. 80
* 95 Yo confidence interval. "Reference catogory. RR: relative risk.
Table 3 Estimation of age-adjusted relative risk of peptic ulcer in gastritis. Data from Sipponen et ~ 2 1 . ~ Type of chronic gastritis
Risk of peptic ulcer (RR)*
Normal antral and corpus mu-
1"
cosa
Chronic antral gastritis or pangastritis (without atrophy in the corpus mucosa)
8.5 (7.0-20.0)
Chronic corpus gastritis with moderate or severe atrophy in the corpus mucosa
0.2 (0.06-0.6)
Chronic antral gastritis with
18.8(9.4-37.7)
Peptic ulcer disease
moderate or severe atrophy in the antral mucosa Chronic pangastritis with severe or moderate atrophy in both antral and corpus mucosa
In chronic corpus gastritis with severe atrophy (former A type of chronic gastritis), the risk of GCA is estimated to be 3-4 times higher than the GCA risk in the general population, or in the subjects with normal This risk may be even higher (18 fold) in chronic antral gastritis with severe atrophy, or in gastritis in which chronic inflammation and severe atrophy concurrently occur in antrum and corpus (pangastritis with severe antral and corpus atrophy).47In pangastritis with severe antral and corpus atrophy, the risk of GCA is considered to be a multiplicant of the marginal risks in antrum and corpust7 being thus several tens of times higher than in subjects with a normal stomach. In terms of cumulative risk, the studies in Finland suggest that the likelihood of GCA may be 30-50 per cent within the following 10-30 years, if the subject is a male, and has gastritis with severe atrophy in antrum, or simultaneously in both antrum and c0rpus.4~T h e corresponding risks in females are somewhat lower, but are still noteworthy. The epidemiological findings of a relationship between HP, chronic gastritis, atrophy, and GCA, suggest that the GCA can be considered, at least in some instances, a late complication of the HP infection. The sequence from gastritis through mucosal atrophy to an overt GCA is, however, complex and multifactorial, and, in addition, this pathway may concern only 30-40 per cent of all GCA cases, that is, the IGCA cases which comprises approximately 40 per cent of all GCA. The GCA of diffuse type, comprising another 40 per cent of the GCA, does not show a clear association with chronic gastritis accompanying atrophy. In addition, the risk of development of GCA is strongest in severe grades of atrophy in which conditions the prevalence and colonization of H P are lowest, suggesting that, in the genesis of GCA, the HP has no direct role in the initiation or modulation of the GCA itself (Table 2).
3.1 (0.7-14)
* 95"/,, confidence interval. "Reference category. RR: relative risk. Gastric cancer Chronic gastritis is a precancerous condition and seems to be particularly related to gastric carcinoma (GCA) of the intestinal type (IGCA).1-3 The prevalence of gastritis with advanced atrophic alterations, with metaplasias, and with dysplastic epithelial changes are more common than expected in IGCA Furthermore, a long list of direct follow-up studies shows that gastritis and gastritisassociated precancerous lesions precede for years the formation of clinically overt carcinomas.2
In many earlier and recent studies, gastritis has been shown to be more common than expected in duodenal (DU) and gastric ulcer (GU) patient^.^'^^-^^ Gastritis seems to also precede the formation of peptic suggesting that gastritis is a real risk factor for the ulcer disease, instead of being a result of the ulcer itself. The role of gastritis in ulcer diseases is complex: gastritis may either increase or decrease the ulcer risk, depending upon the grade and the topographic type of gastritis. Gastritis and atrophy in the antrum tend to increase the risk of peptic ulcer while gastritis with atrophy in the corpus mucosa tends to decrease this r i ~ k . ~ . ~ ~ Recent case-control studies have suggested that the risk of peptic ulcer, of D U in particular, is approximately 10 times higher in gastritis in general, than in subjects with a normal This risk seems to differ with regard to type of ulcer (DU vs. GU), gender, age, and grade or extent of inflammation and atrophy, so that the DU risk is particularly high (6 to 16 fold compared to the risk in subjects with a normal stomach) in males with an antral gastritis (antral gastritis or pangastritis without coexistent atrophy of the corpus mucosa) whereas the G U risk may be even higher (24 to 32 fold) in the presence of gastritis with atrophic antral change^.^'^^
The Sydney System: Epidemiology of chronic gastritis
In a direct follow-up study the 10 year cumulative ulcer risk (the risk of D U in particular) in middle-aged males has been estimated to be 20-30%, when the corresponding risk in males without gastritis is less than 1To.s3These investigations among many others may indicate that, if the NSAID-associated ulcers are excluded, the likelihood and risk of a peptic ulcer might be extremely low in subjects who do not have gastritis, but is, in contrast, remarkably high in some subjects with “specific” types of chronic gastritis. In contrast to chronic antral gastritis, chronic corpus gastritis with atrophy tends to lower the likelihood of ulcer, in parallel with an increase in grade of the corpus atrophy.s In our own studies, the 10 year cumulative risk of peptic ulcer (DU in particular) has been estimated to be less than 1% if moderate or severe atrophic changes occur in the corpus m ~ c o s a . ~ ~ Chronic korpus gastritis with accompanying atrophy seems to affect and modulate the course of peptic ulcer disease. Studies in Estonia and Poland have suggested that an existing ulcer may heal spontaneously with a development and progression of chronic corpus gastritis to stages in which inflammation is accompanied by marked atrophic a l t e ~ a t i o n ,pointing ~ ~ * ~ ~to the possibility that the “activity” of ulcer disease follows the natural course of gastritis; that is, gastric ulcer disease may have a life span of 10-15 years, during which time period the ulcer may repeatedly come and go, but will finally This may be the case at least in some of the patients with gastric ulcer in the angulus, or in the gastric corpus. A corresponding time-dependent progression and development of corpus atrophy seems to be rare or absent in the course of D U disease.s6 The persistence of normal, nonatrophic corpus mucosa in D U patients may result in permanently normal or high acid secretion of acid, and in life-long chronicity of the D U disease in these patients.
249
tric diseases. In most instances, gastritis seems to be a bacterial (microbial) disease. It begins as long-lasting, chronic inflammatory reaction directed against Helicobacter pylori (HP), or occasionally against other spiral bacteria, which colonize in the space between the surface epithelium and the mucuos layer. Gastritis may, irrespectively of the HP-related or HP-independent origin, progress to an atrophy (chronic gastritis with atrophy) in the underlying mucosa. Prevalence of gastritis increases with increase in age, but great variations exist in the age-specific prevalence and in mean age of onset of the gastritis in different populations. A high rate and an early onset of the HP-related gastritis associates with low socio-economic status. Chronic gastritis, and the gastritis with atrophy in particular, may interfere with the function of the affected gastric mucosa, and may subsequently increase or decrease the risk of some gastric diseases, such as cancer and peptic ulcer. Both antral and corpus gastritis with coexistent severe atrophic changes have been shown to be associated with an increased risk of gastric cancer. I n addition, gastritis seems to also play an important role in the pathogenesis of peptic ulcer. Virtually all patients with D U and GU have coexisting and preceding gastritis. T h e cumulative risk of ulcer has been estimated to be high in subjects with gastritis, but, in contrast, to be low in subjects who have normal gastric mucosa.
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2.
Other diseases Some other gastric diseases, such as gastric polyps or carcinoids, are also rather commonly associated with CG.57*s8 The pathogenesis and the morphogenesis of these diseases could be seen to be caused by gastritis and by subsequent atrophy. Small multifocal carcinoid tumours in chronic gastritis with severe corpus atrophy are related to achlorhydria caused by a total atrophy of the corpus mucosa. I n connection with normal antral mucosa, achlorhydria causes hypergastrinaemia. Subsequently, hypergastrinaemia may exert a trophic stimulus on proliferation of the oxyntic endocrine cells, which may correspondingly lead to a rise in risk of development of overt carcinoid turnours.” Pernicious anaemia is another important late complication of CG, and is always associated with severe (total) atrophy of the gastric body mucosa (corpus gastritis with severe atrophy in the corpus mucosa), and with impairment of the corpus mucosa to secrete intrinsic factor.41
SUMMARY Chronic gastritis is a common disease which forms an important background to the pathogenesis of several gas-
3.
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6.
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W. Effect of age on the frequency of active Campylobacter pylori infection diagnosed by the (13C) urea breath test in normal subjects and patients with peptic ulcer. 3. Infect. Dis. 1988; 157: 777-80. 34. MORRIS A., NICHOLSON G., LLOYDG., HAINESD., ROGERS
D. Seroepidemiology of Campylobacter pyloriA. & TAYLOR dis. N.Z. Med. 3. 1986; 99: 657-9. 35. PEREZ-PEREZ G., DWORKIN B. M., CHODESJ. E. & BLASER M. J. Campylobacter pylori antibodies in humans. Ann. Int. Med. 1988; 109: 11-7. 36. MITCHELLH. M., LEEA., BERKOWICZ J. & BOROBY T. The use of serology to diagnose active Campylobacter pylori infection. Med. 3. Aust. 1988; 149: 604-9. D. Y., ADAME., KLEINP. D. et al. Epidemiology of 37. GRAHAM Campylobacter pylori infection. Gastroenterol. Clin. Biol. 1989, 13: 84-89B. 38. SITASF., FORMAN D., CHENJ., NEWELLD. & STACEY A. Prevalence of infection with Campylobacter pylori in China: Results from a large correlation study in 46 regions. Klin. Wslthr. 1989; 67 (Suppl. 18): 64. P., CUELLO C. & DUQUE E. Carcinoma and intestinal 39. CORREA metaplasia in Colombian migrants. 3.Narl Cancer Inst. 1970; 44: 297-306. G., HAENSZEL W. & LOCKEF. Epidemio40. STEMMERMANN
logic pathology of gastric ulcer and gastric carcinoma among Japanese in Hawaii. 3. Natl Cancer Inst. 1977; 58: 13-20, 41. VARISK. & ISOKOSKI M. Screening of type A gastritis. Ann. Clin. Res. 1981; 13: 133-8. P., VALLEJ., VARISK., KEKKIM. & SIURALA M. 42. SIPPONEN Fasting levels of serum gastrin in different functional and morphological states of the antro-fundal mucosa. An analysis of 860 subjects. Scand. 3.Gasrroenterol. 1990; 25: 513-9. 43. JANSENJ. B., SCHAARDENBURG D. J., LAMPERTSE. J., C. B. Low antral gastrin BOOMGAART D. M. & LAMMERS content and impaired bombesin stimulated gastrin secretion in the intestinal type of gastric cancer. Dig. Dis. Sci. 1986; 31: (Suppl. 10): 4s. 44. LEVIS., BEARDSHALL K. & SWIFTI. et al. Campylobacter pylori and duodenal ulcers: the gastrin connection. Gut 1989; 30: A1443. 45. SAROSIEK J., SLOMIANY A. & SLOMIANY B. L. Evidence for weakening of gastric mucus integrity by Campylobacter pylori. Scand. 3. Gastroenterol. 1988; 23: 585-90. K., IHAMAKI T., TAMM A. er al. Upper abdominal 46. VILLAKO complaints and gastritis. Ann. Clin. Res. 1984; 16: 192-4. P., KEKKIM., HAAPAKOSKI J., IHAMAKIT . & 47. SIPPONEN SIURALA M. Gastric cancer risk in chronic atrophic gastritis: statistical calculations of cross-sectional data. Int. 3.Cancer 1985; 35: 173-7. 48. VARISK. Surveillance of pernicious anaemia. In: Sherlock P., Morson B. C., Barbara L. & Veronesi U., eds, Precancerous
Lesions of the Gastrointestinal Tract. Raven Press, New York. 1983; 189-94. 49. SIPPONEN P., ~ R Y N E NM., KAARIAINEN I., KETTUNENP., HELSKET. & SEPPALAK. Chronic antral gastritis, Lewisa+
phenotype, and male sex as factors in predicting coexisting duodenal ulcer. Scand. 3. Gastroenterol. 1989; 24: 581-8.
The Sydney System: Epidemiology of chronic gastritis
50. GEARM.W. L., TRUELOVE S. C. & WHITEHEAD R. Gastric ulcer and gastritis. Gut 1972; 12: 639-45. 51. OVERGAARD NIELSENH.,MUNOZJ. D., KRONBORG 0. & ANDERSEN D. The antrum in duodenal ulcer patients. Scand. 3.Gastroenterol. 1981;16:491-3. 52. SCHRAGER J., SPINKR. & MITRAS. The antrum in patients with duodenal and gastric ulcers. Gut 1967;8: 497-508. P.,VARISK., FRAKIO., KORRIU-M., SEPPALA K. 53. SIPPONEN & SIURALAM. Cumulative 10-year risk of symptomatic duodenal and gastric ulcer in patients with or without chronic gastritis. A clinical follow-up study of 454 outpatients. S c a d . 3.Gascroenterol. 1990; 25: 966-73. 54. MAAROOSH-I.,SALUPEREV., UIBO R., KEKKI M. & SIPPONEN P.Seven-year follow-up study of chronic gastritis in gastric ulcer patients. Scand. 3. Gastroenterol 1985; 20: 198-204.
25 1
55. LASZEWICZ W., GABRYELEWICZ A,, SIPPONEN P., KEKKI M., M. Gastric ulcer and gastritis: results of LAXEN F. & SIURALA short term follow-up examinations. Hepatogastroenterology 1987; 34: 265-8. 56. KEKKIM., SIPPONEN P. & SIURALA M. Progression of antral and body gastritis in patients with active and healed duodenal ulcer and duodenitis. Scand.3.Gastroenterol. 1984;19:382-8. 57. LAXENF., KEKKIM., SIPPONENP. & SIURALAM. T h e gastric mucosa in stomachs with polyps: morphologic and dynamic evaluation. Scand. 3.Gastroenterol 1983;18:503-1 1. 58. SJOBLOM S-M., HAAPIAINEN R., MIETTINEN M. & JARVINEN H. Gastric carcinoid tumours and atrophic gastritis. Acta Chir. Scand. 1987; 153: 37-43. 59. HAKANSON R.,B~TTCHER G., SUNDLER F. & VALLGREN S. Activation and hyperplasia of gastrin and enterochromffilike cells in the stomach. Digestion 1986;35 (Suppl. 1): 23-41.
Journal of Castromterology and Hepatology (1991) 6, 244-251
The Sydney System: Epidemiology and natural history of chronic gastritis P E N T T I SIPPONEN, M A T T 1 KEKKI A N D MAX SIURALA Department of Pathology, Jorvi Hospital, Espoo, Finland
INTRODUCTION Chronic gastritis (CG) has been a target of research for more than 100 years. Until now, its nature and relationship with gastric diseases have remained mysterious. The significance of C G has been re-emphasized, however, in recent years, because it has become apparent that C G is commonly associated with important gastric diseases such as gastric carcinoma or peptic ulcer diseases.’-’ In addition, most recent studies suggest that in most patients C G is a bacterial (microbial) disease, and that a successful treatment of the infection results in improvement of gastritis.6-10This has important therapeutic implications, particularly with respect to peptic ulcer disease.
NATURAL C O U R S E Chronic gastritis starts as an accumulation of inflammatory round cells in lamina propria of the gastric mucosa. These round cells are immunocompetent cells, mainly lymphocytes and IgA, IgG and IgM secreting plasma cells. Granulocytes often accompany CG and invade the lamina propria and the surface epithelium focally or diffusely (“active chronic gastritis”).ll This inflammatory stage of CG is commonly termed and referred to as “superficial gastritis” in the former literature. I n a number of subjects, gastritis may further progress to atrophy, “atrophic gastritis”, this stage of the process being characterized by an increasing loss of normal glands and by a growth of new metaplastic glands (intestinal, pseudopyloric metaplasias) in the underlying affected mucosa.” The C G is a peculiarly stable, persistent inflammatory response. Recent evidence suggests that this response is directed against specific bacterial organisms, Helicobacter pylori (HP), or, more rarely, against some other spiral organisms which colonise the surface of the gastric mucosa. 6*12 Without specific treatment CG is a life-long disease.13 However, in some rare patients C G may slow down and even heal, particularly in the antral mucosa. More often, C G remains stable, or progresses to gastritis with atrophy. l3 The long-term biopsy follow-up of Finnish and Estonian outpatient and population samples provide rough estimates of the natural course of C G (Table l).14-17 In some instances, C G appears in childhood, but is of slight degree and may heal spontaneously.” The next event is the appearance of CG in 15-30 year age group. In this phase,
C G affects both antrum and corpus, but usually affects the antrum more severely. Typically, at this age range, gastritis is a simple chronic inflammation and is accompanied by the presence of H P and serological antibody response against this bacterium in most cases.18 T h e diffuse HP-related chronic “pangastritis” (chronic gastritis in antrum and body) continues with increasing severity in middle age range ( 3 0 4 0 years) and is still present in the old age range (>61 years). In the development of atrophy there appears a dispersion of the process to three dissimilar topographic phenot y p e ~ in : ~ some ~ cases the distinct atrophic changes are limited to the antrum (antral gastritis with atrophy; former “B gastritis”), corpus (corpus gastritis with atrophy; former “A gastritis”), or they may affect antrum and corpus simultaneously (pangastritis with antral and corpus atrophy; former “AB gastritis”). The mean prevalence of the different phenotypes in the expression of C G in a Finnish adult population sample (mean age 46 years) is presented in Fig. 1. The final stage in the development of atrophy is total gastric atrophy. Although the speed of progression of Table 1 Summary of characteristics of chronic gastritis in different age groups of the general population Age group
Features of gastritis
Childhood ( < 15 years)
HP-associated antral gastritis. Gastritis is rare and mild. Tendency to heal.
Young age (15-30 years)
HP-associated antral gastritis or pangastritis are rather common. Atrophy is rare.
Middle age (30-60years)
HP-associated antral gastritis or pangastritis are common. Appearance of topographically different types of chronic gastritis with atrophy, that is, antral, corpus or pangastritis with coexistent atrophic changes in the underlying mucosa
Old age (61 +years)
All types of gastritis with atrophy are common. Autoimmune-type corpus gastritis with severe atrophy is not infrequent.
Correspondence: Dr P. Sipponen, Department of Pathology, Jorvi Hospital, 02740 Espoo, Finland. Accepted for publication 14 December 1990.
The Sydney System: Epidemiology of chronic gastritis
245
gastritis varies between individuals, in general, the process is very slow, and the time needed for the development of total gastric atrophy may be several decades. Studies in Finland suggest that the mean annual transition risk (per cent/year)of a subject to get antral or corpus gastritis is about 3 per 100, and is approximately of the same magnitude in the further progression of gastritis from simple chronic gastritis without atrophy to that one which accompanies atrophic changes (chronic gastritis with atrophy) (Fig. 2). In the further progression of gastritis to even more atrophic stages, it may be that the speed increases along with the increase in extent of the p r o c e ~ s . ~ ~ ' ~ ~
Chronic antral gastritis with or without accompanying atrophy is clearly HP-related. The bacteria are, however, usually absent in chronic corpus gastritis (corpus gastritis with severe corpus atrophy in particular)?l On the other hand, serum antibodies for HI? may occur also in this typeZZ but are seldom present, indicating that the p u r e corpus gastritis is unlikely to be HP-dependent in origin. On the whole, chronic corpus gastritis with moderate or severe atrophy (former "A gastritis") represents only a minor proportion (1-2*,) of subjects in the entire pool of CG patients, suggesting that most CG cases are linked with the acquisition of an HP infection (Table 1, Fig. 1).
GASTR IT I S WITHOUT ATROPHY
WITH ANTRAL ATROPHY 6%
I
56%
WITH CORPUS ATROPHY 2%
\
WITH ANTRAL AND CORPUS 4% ATROPHY
Figure 1 Prevalenceof different types of chronic gastritis in a Finnish population sample (males and females together; mean age 46 years; data collected in 1975-77). Data from Kekki et ~ 1 . ' ~
ANTRAL MUCOSA
3.5 OO/
CORPUS MUCOSA
3.3Q/'
3.3 %
Figure 2 Scheme presenting the mean annual risk to a subject of contracting chronic gastritis and, further, of contracting chronic gastritis with coexistent atrophy in the general population. Data from studies on gastritis in the general asymptomatic Finnish population.20
P. Sipponen et al.
246
Although CG is virtually always related to HP at the start of the process, the further progression of CG from ga.;tritis without atrophy t o that one which accompanies atrophy seems to be less HP-dependent.z1.23The prevalence and grade of HP colonization steadily decrease parallel with the progression of atrophy. This indicates that factors other than bacteria may also influence the course of CC ; . 2 J Such Iic.tors can be genetic, macro-environmental (cg., nitrogen containing compounds, dietary factors, drugs) or micro-environmental (e.g., duodenogastric reflux, intragastric formation of nitrosocompounds) although the evidence from such processes is still far from convincing. Genetic factors certainly affect the course of CG, although the role of these factors, may vary in different topographical types of g a ~ t r i t i s . ~In~ the . ~ ~pathogenesis -~~ of corpus gastritis with atrophy (“A gastritis”), there is a dominantly inherited major factor which determines the ~ development of atrophy of the corpus m u c o ~ a . ’This factor seems to operate alone or in association with other closely related factors (genes).15 There also is some evidence that a recessively inherited parameter exists in the pathogenesis of chronic antral gastritis with atrophy (“B g a s t r i t i ~ ” ) .Genetic ~ ~ . ~ ~ factors may also occur in the genesis of pangastritis (“AB gastritis”) but these factors are even less well known.” ‘Thepresence of specific mechanisms in the pathogenesis of the three topographic phenotypes of chronic gastritis with atrophy have been demonstrated by the family behaviour of gastritis (15, 25). When a phenotype of chronic gastritis with accompanying atrophic alterations is chosen as an index, it appears that the same phenotype tends to occur more often than expected in the first degree relatives of the index subject, and the other phenotypes are less common than expected.1s In addition to the three topographic types in the expression and progression of gastritis, C G may also show heterogeneity in other respects. Gastritis, particularly gastritis with atrophy of mild degree, may be markedly patchy in antrum and corpus. Some areas of the stomach, like the angulus and the lesser curve, seem to be more liable to atrophy than the other In addition, the progression of gastritis in the antrum and corpus may occur in particular directions; as pyloro-cardiac or cardio-pyloric extensions of the original lesion.2s With regard to gender, there are no distinct differences in the natural course of C G between males and fern ale^.'^*^^ However, some studies tentatively suggest that the male gender shows a slightly higher liability toward gastritis than the female gender, but only at very early stages of the process.15
PREVALENCE The prevalence of CG in the population is strongly dependent on age. This total prevalence of C G and the prevalence of CG accompanied b y atrophic stages in antrum and corpus increase with age (Fig. 3). C G is rare in children in Western countries, but its frequency rises later rather linearly by age. On average, over one half of the population, even in industrialised Western countries, has C G of some degree in age groups above 50-60 years. Population-based reliable endoscopical and histological studies on gastritis are few in number. A group of studies,
100
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--z o
80
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?!
40
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Figure 3 Age-specific prevalence of chronic gastritis (M) with and ( E l ) without atrophy in antral (upper picture) and corpus (lower picture) mucosa. From a sample representing the general Finnish population.I9
presenting the age-specific prevalence of C G in five These data European countries is shown in Fig. 4.19r29-31 demonstrate that CG is, indeed, very common in all populations in general, and that the greatest differences in prevalence of C G seem to occur in young and middle age. Extrapolation of the data in Fig. 4 would suggest that nearly the whole population in all five countries may have C G in age groups of 80 years or above. The detection of serum HP-antibodies has provided new possibilities for comprehensive epidemiological studies on HP-related gastritis. These studies have shown good concordance between endoscopically and serologically determined gastritis, and have confirmed that the frequencies of HP infection and of subsequent gastritis are usually very high, but that the rates of HP infection and gastritis also vary enormously in different parts of the world (Fig. 4).32-36 Based on these epidemiological data, it is likely that the prevalence of HP-related gastritis is dependent on the socioeconomic status of the pop~lation,~’ suggesting that an acquisition of the infection seems to be frequent in populations, or in countries, with a low standard of environmental hygiene, compared with those with high standards of living. It has become apparent, further, that in addition to the total C G prevalence, the mean age of onset of the HP infection may also be an important epidemiological variable.33p37Populations with high CG prevalence usually show an early onset of the infection, and vice versa (Fig. 4). It is tempting to speculate that chronic gastritis with
The Sydney System: Epidemiology of chronic gastritis
247
ESTONIA
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Figure 4 Age-specific prevalence of (a) endoscopically and histologically determined gastritis and (b) age-specific prevalence of HP antibodies in different populations and c o u n t r i e ~ . ’ ~ ~ ~ ~ - ~ ~
marked atrophic changes is common in such populations in which a great proportion of subjects are infected at an early age, and in which time is, therefore, long enough for the development of atrophy in a significant proportion of the population. Correspondingly, it may be anticipated that the rate of the gastritis-related diseases is also high in such populations. This seems, indeed, to be the case. In a study in different provinces of China it has been shown recently that a high prevalence and an early onset of HP infection correlates with high incidence of gastric cancer.38 These observations are in good agreement with the earlier endoscopical and histological findings that a positive relationship exists between incidence of gastric cancer and degree and prevalence of chronic gastritis and atrophy (and intestinal metapla~ia).”*~~
RELATION OF FUNCTION OF GASTRIC MUCOSA Chronic gastritis, particularly chronic gastritis which accompanies atrophic changes in the underlying mucosa, profoundly affects the function of the stomach. Pentagastrin stimulated acid output is decreased already in mild corpus atrophy, and it decreases linearly with further loss of normal oxyntic glands, i.e., with progression of atrophy similar decrease is also evident in in the corpus m ~ c o s aA. ~ ~ fasting levels of serum pepsinogen I and in the output of intrinsic factor, suggesting that the atrophy leads to a general impairment in physiological functions of the gastric m ~ c o s a . ~ ~ The relationship between histology and function is not limited to the corpus mucosa only. A corresponding rela-
tionship exists also between antral gastritis and function of of atrophy in antral the antral m u c o ~ a ; development ~~*~~ mucosa results in decreased fasting and stimulated outputs of gastrin from antral G cells. Recent observations suggest that the H P itself may also have gastritis-independent actions on gastric functions.44 The HP is a urease-rich bacterium and produces ammonia from endogenous urea: a consequence may be that a HPdependent production of base in the stomach is high enough to neutralize acid produced in fasting conditions, thus resulting further in a release of gastrin from the antral G cells. Gastritis and H P colonization may impair mucosal resistance, although our knowledge in this respect is scanty.6 An acute erosive inflammation in HP-related gastritis may lower the epithelial integrity. The bacterium itself may also have noxious effects on the mucous layer and on the surface epithelial cells: the H P may secrete cytotoxic substances and enzymes with proteolytic and lipolytic proper tie^.^^
RELATIONSHIP TO GASTRIC DISEASES CG is asymptomatic in general but may be associated with several symptomatic gastric diseases.*946 The biological and clinical importance of chronic gastritis lies in that gastritis seems to be strongly associated with some important gastric diseases, such as gastric cancer or peptic ulcer disease, or, at least, is linked with an increased risk of these disorders. Estimations of the risk of peptic ulcer and gastric cancer in chronic gastritis are presented in Tables 2 and 3.
P . Sipponen et al.
248
Table 2 Estimation of age-adjusted relative risk of gastric cancer. Data from S a r o ~ i e k ~ ~ Type of chronic gastritis
Risk of gastric cancer (RR)*
Normal antral and corpus mu-
1"
cosa, or chronic pangastritis inrthout cncYi\Icrit
atrophy)
Chronic corpus gastritis with severe atrophy in the corpus
4.6 (l.slO.9)
muc05a
Chronic antral gastritis with severe atrophy in the antral mucosa
18.1(4.1-80.1)
Chronic pangastritis, with severe atrophy in both antral and corpus mucosa
approx. 80
* 95 Yo confidence interval. "Reference catogory. RR: relative risk.
Table 3 Estimation of age-adjusted relative risk of peptic ulcer in gastritis. Data from Sipponen et ~ 2 1 . ~ Type of chronic gastritis
Risk of peptic ulcer (RR)*
Normal antral and corpus mu-
1"
cosa
Chronic antral gastritis or pangastritis (without atrophy in the corpus mucosa)
8.5 (7.0-20.0)
Chronic corpus gastritis with moderate or severe atrophy in the corpus mucosa
0.2 (0.06-0.6)
Chronic antral gastritis with
18.8(9.4-37.7)
Peptic ulcer disease
moderate or severe atrophy in the antral mucosa Chronic pangastritis with severe or moderate atrophy in both antral and corpus mucosa
In chronic corpus gastritis with severe atrophy (former A type of chronic gastritis), the risk of GCA is estimated to be 3-4 times higher than the GCA risk in the general population, or in the subjects with normal This risk may be even higher (18 fold) in chronic antral gastritis with severe atrophy, or in gastritis in which chronic inflammation and severe atrophy concurrently occur in antrum and corpus (pangastritis with severe antral and corpus atrophy).47In pangastritis with severe antral and corpus atrophy, the risk of GCA is considered to be a multiplicant of the marginal risks in antrum and corpust7 being thus several tens of times higher than in subjects with a normal stomach. In terms of cumulative risk, the studies in Finland suggest that the likelihood of GCA may be 30-50 per cent within the following 10-30 years, if the subject is a male, and has gastritis with severe atrophy in antrum, or simultaneously in both antrum and c0rpus.4~T h e corresponding risks in females are somewhat lower, but are still noteworthy. The epidemiological findings of a relationship between HP, chronic gastritis, atrophy, and GCA, suggest that the GCA can be considered, at least in some instances, a late complication of the HP infection. The sequence from gastritis through mucosal atrophy to an overt GCA is, however, complex and multifactorial, and, in addition, this pathway may concern only 30-40 per cent of all GCA cases, that is, the IGCA cases which comprises approximately 40 per cent of all GCA. The GCA of diffuse type, comprising another 40 per cent of the GCA, does not show a clear association with chronic gastritis accompanying atrophy. In addition, the risk of development of GCA is strongest in severe grades of atrophy in which conditions the prevalence and colonization of H P are lowest, suggesting that, in the genesis of GCA, the HP has no direct role in the initiation or modulation of the GCA itself (Table 2).
3.1 (0.7-14)
* 95"/,, confidence interval. "Reference category. RR: relative risk. Gastric cancer Chronic gastritis is a precancerous condition and seems to be particularly related to gastric carcinoma (GCA) of the intestinal type (IGCA).1-3 The prevalence of gastritis with advanced atrophic alterations, with metaplasias, and with dysplastic epithelial changes are more common than expected in IGCA Furthermore, a long list of direct follow-up studies shows that gastritis and gastritisassociated precancerous lesions precede for years the formation of clinically overt carcinomas.2
In many earlier and recent studies, gastritis has been shown to be more common than expected in duodenal (DU) and gastric ulcer (GU) patient^.^'^^-^^ Gastritis seems to also precede the formation of peptic suggesting that gastritis is a real risk factor for the ulcer disease, instead of being a result of the ulcer itself. The role of gastritis in ulcer diseases is complex: gastritis may either increase or decrease the ulcer risk, depending upon the grade and the topographic type of gastritis. Gastritis and atrophy in the antrum tend to increase the risk of peptic ulcer while gastritis with atrophy in the corpus mucosa tends to decrease this r i ~ k . ~ . ~ ~ Recent case-control studies have suggested that the risk of peptic ulcer, of D U in particular, is approximately 10 times higher in gastritis in general, than in subjects with a normal This risk seems to differ with regard to type of ulcer (DU vs. GU), gender, age, and grade or extent of inflammation and atrophy, so that the DU risk is particularly high (6 to 16 fold compared to the risk in subjects with a normal stomach) in males with an antral gastritis (antral gastritis or pangastritis without coexistent atrophy of the corpus mucosa) whereas the G U risk may be even higher (24 to 32 fold) in the presence of gastritis with atrophic antral change^.^'^^
The Sydney System: Epidemiology of chronic gastritis
In a direct follow-up study the 10 year cumulative ulcer risk (the risk of D U in particular) in middle-aged males has been estimated to be 20-30%, when the corresponding risk in males without gastritis is less than 1To.s3These investigations among many others may indicate that, if the NSAID-associated ulcers are excluded, the likelihood and risk of a peptic ulcer might be extremely low in subjects who do not have gastritis, but is, in contrast, remarkably high in some subjects with “specific” types of chronic gastritis. In contrast to chronic antral gastritis, chronic corpus gastritis with atrophy tends to lower the likelihood of ulcer, in parallel with an increase in grade of the corpus atrophy.s In our own studies, the 10 year cumulative risk of peptic ulcer (DU in particular) has been estimated to be less than 1% if moderate or severe atrophic changes occur in the corpus m ~ c o s a . ~ ~ Chronic korpus gastritis with accompanying atrophy seems to affect and modulate the course of peptic ulcer disease. Studies in Estonia and Poland have suggested that an existing ulcer may heal spontaneously with a development and progression of chronic corpus gastritis to stages in which inflammation is accompanied by marked atrophic a l t e ~ a t i o n ,pointing ~ ~ * ~ ~to the possibility that the “activity” of ulcer disease follows the natural course of gastritis; that is, gastric ulcer disease may have a life span of 10-15 years, during which time period the ulcer may repeatedly come and go, but will finally This may be the case at least in some of the patients with gastric ulcer in the angulus, or in the gastric corpus. A corresponding time-dependent progression and development of corpus atrophy seems to be rare or absent in the course of D U disease.s6 The persistence of normal, nonatrophic corpus mucosa in D U patients may result in permanently normal or high acid secretion of acid, and in life-long chronicity of the D U disease in these patients.
249
tric diseases. In most instances, gastritis seems to be a bacterial (microbial) disease. It begins as long-lasting, chronic inflammatory reaction directed against Helicobacter pylori (HP), or occasionally against other spiral bacteria, which colonize in the space between the surface epithelium and the mucuos layer. Gastritis may, irrespectively of the HP-related or HP-independent origin, progress to an atrophy (chronic gastritis with atrophy) in the underlying mucosa. Prevalence of gastritis increases with increase in age, but great variations exist in the age-specific prevalence and in mean age of onset of the gastritis in different populations. A high rate and an early onset of the HP-related gastritis associates with low socio-economic status. Chronic gastritis, and the gastritis with atrophy in particular, may interfere with the function of the affected gastric mucosa, and may subsequently increase or decrease the risk of some gastric diseases, such as cancer and peptic ulcer. Both antral and corpus gastritis with coexistent severe atrophic changes have been shown to be associated with an increased risk of gastric cancer. I n addition, gastritis seems to also play an important role in the pathogenesis of peptic ulcer. Virtually all patients with D U and GU have coexisting and preceding gastritis. T h e cumulative risk of ulcer has been estimated to be high in subjects with gastritis, but, in contrast, to be low in subjects who have normal gastric mucosa.
REFERENCES 1 . NAGAYO T. Precursors of human gastric cancer. Their fre-
2.
Other diseases Some other gastric diseases, such as gastric polyps or carcinoids, are also rather commonly associated with CG.57*s8 The pathogenesis and the morphogenesis of these diseases could be seen to be caused by gastritis and by subsequent atrophy. Small multifocal carcinoid tumours in chronic gastritis with severe corpus atrophy are related to achlorhydria caused by a total atrophy of the corpus mucosa. I n connection with normal antral mucosa, achlorhydria causes hypergastrinaemia. Subsequently, hypergastrinaemia may exert a trophic stimulus on proliferation of the oxyntic endocrine cells, which may correspondingly lead to a rise in risk of development of overt carcinoid turnours.” Pernicious anaemia is another important late complication of CG, and is always associated with severe (total) atrophy of the gastric body mucosa (corpus gastritis with severe atrophy in the corpus mucosa), and with impairment of the corpus mucosa to secrete intrinsic factor.41
SUMMARY Chronic gastritis is a common disease which forms an important background to the pathogenesis of several gas-
3.
4. 5.
6.
quencies and histological characteristics. In: Farber E., ed., Pathophysiology of Carcinogenesis in Digestive Organs. University Park Press, Baltimore. 1977; 151-60. SIURALA M., VARISK. & SIPPONEN P. Carcinogenesis in the foregut. Part 2. Gastric carcinoma. In: Baron J. H., Moody F. G., eds, Foregut. Butterworths, London. 1981; 276-312. CORREA P. Chronic gastritis and gastric cancer. In: Ming S. C., ed., Precursors of Gastric Cancer. Praeger Publishers, New York. 1984; 105-16. CHELIR., PERASSO A. & GIACOSA A. Gastritis. SpringerVerlag, Berlin. 1987. SIPPONEN P., SEPPALAK., ~ R Y N E NM., HELSKET. 8t KETTUNEN P. Chronic gastritis and gastroduodenal ulcer: a case control study on risk of coexisting duodenal or gastric ulcer in patients with gastritis. Gut 1989; 30: 922-9. GRAHAM D. Y. Campylobacter pylori and peptic ulcer disease.
Gastroenterology 1989; 96: 615-25. J. R. & MARSHALL B. J. Unidentified curved bacilli 7. WARREN on gastric epithelium in active chronic gastritis.Lancet 1983; i: 1273-5. 8. RAUWSE. A. J., LANGENBERG W., HOUTHOFF H. J., ZANEN H. C. & TYTGAT G. N . J. Campylobacter pylori-associated chronic active gastritis. A prospective study of its prevalence and the effects of antibacterial and antiulcer treatment. Gastroenterology 1988; 94: 3 3 4 0 . 9. MARSHALL B. J., GOODWIN C. S., WARRENJ. R. et al.
Prospective double-blind trial of duodenal ulcer relapse after eradication of Campylobacter pylori. Lancet 1988; ii: 1437-42. 10. LEEF. I., SAMLOFF M. I. & HARDMAN M. Comparison of tripotassium di-citrato bismuthate tablets with ranitidme in healing and relapse of duodenal ulcers. Lancet 1985; i: 1299-302.
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